Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by an increased permeability of brain capillary endothelial cells to macromolecules and by an increased extracellular space and brain water. Although the pathogenesis of vasogenic edema following brain ischemia and injury are multifactorial, the basic mechanism of this type of edema is dependent upon alterations in the structural and functional integrity of brain endothelial cells. We have postulated that the free arachidonic acid and oxygen-derived radicals, superoxide radicals in particular, are involved. We now propose to test hypothesis using both in vivo animal models and in vitro brain capillaries and brain capillary-derived endothelial cells. Our specific aims are: (1) To establish the involvement of superoxide radicals in animal models of vasogenic brain edema obtained with intracerebral injection of arachidonic acid or xanthine oxidase hypoxanthine. (2) To establish the role of superoxide radicals in ischemic brain edema following occlusion of middle cerebral artery in the rat. We will employ liposome- entrapped superoxide dismutase (which has recently been used successfully by us to reduce the level of superoxide radicals and ameliorate blood brain barrier permeability changes and vasogenic edema in rats with cold-induced brain injury) to study their beneficial effects in ameliorating ischemic brain edema. (3) To investigate the involvement of our postulated "polyunsaturated fatty acids-oxygen radical cycle or cascade" in isolated brain capillaries in vitro under incubation conditions simulating ischemia and hypoxia. The liposome-facilitated uptake of superoxide dismutase into brain capillaries and the protective mechanisms of the antioxidative enzyme(s) on capillary injury will be delineated. (4) To study the role of superoxide radicals in ischemic injured or arachidonic acid challenged brain capillary endothelial cells. Agents that can increase intracellular content of superoxide dismutase (by means of liposomes), or agents that can promote the intracellular formation of superoxide radicals and reduce the cellular level of superoxide dismutase will be employed to study the sensitivity or resistance of endothelial cells toward stresses induced by ischemia, hypoxia, and chemicals. These oxidative studies have therapeutic implications and will shed light into biochemical mechanisms underlying the pathogenesis of vasogenic edema following ischemia and hypoxia.